• What is BIRC3?
  • BIRC3 in Chronic Lymphocytic Leukemia
  • Clinical Trials

BIRC3

Baculovial IAP repeat containing 3 (BIRC3) is a gene that encodes encodes the protein cellular inhibitor of apoptosis protein 2 (cIAP2), which inhibits apoptosis by binding to tumor necrosis factor receptor-associated factors TRAF1 and TRAF2; cIAP2 is also a negative regulator of NF-κB signaling in B-cells through its ubiquitin-ligase activity, which targets the downstream protein kinase MAP3K14 for degradation by the proteasome (Bertrand et al. 2011; Buggins et al. 2010; Conze, Zhao, and Ashwell 2010; Foà et al. 2013; Li, Yang, and Ashwell 2002; Rossi et al. 2012; Zarnegar et al. 2008; Zhou et al. 2013).

BIRC3 is localized to chromosome 11q22, whose deletion is associated with high risk disease in patients with chronic lymphocytic leukemia. BIRC3 mutations are observed in <5% of patients with CLL (Baliakas et al. 2015; Chiaretti et al. 2014; Cortese et al. 2014; Rossi et al. 2012; Xia et al. 2015), ~11% of patients with Splenic marginal zone lymphoma (Rossi et al. 2011) and 6-10% of mantle cell lymphoma cases (Rahal et al. 2014).

Contributors: Nishitha Reddy, M.B.B.S., MSCI

Suggested Citation: Reddy, N. 2016. BIRC3. My Cancer Genome https://www.padiracinnovation.org/content/disease/chronic-lymphocytic-leukemia/birc3/?tab=0 (Updated February 12).

Last Updated: February 12, 2016

BIRC3 in Chronic Lymphocytic Leukemia

BIRC3 can be altered in several different ways in chronic lymphocytic leukemia (CLL), with most mutations being inactivating (Bertrand et al. 2011; Buggins et al. 2010; Conze, Zhao, and Ashwell 2010; Foà et al. 2013; Li, Yang, and Ashwell 2002; Rossi et al. 2012; Zarnegar et al. 2008; Zhou et al. 2013). These alterations are primarily whole-gene deletions or frameshift or nonsense mutations resulting in the premature truncation of the BIRC3-encoded protein product, cIAP2; this truncation occurs prior to the C-terminal RING domain responsible for the E3 ubiquitin ligase activity of cIAP2 (Bertrand et al. 2011; Buggins et al. 2010; Conze, Zhao, and Ashwell 2010; Foà et al. 2013; Li, Yang, and Ashwell 2002; Rossi et al. 2012; Zarnegar et al. 2008; Zhou et al. 2013). Because one function of cIAP2 is to act as a negative regulator of NF-κB signaling in B-cells by ubquitinating the downstream protein kinase MAP3K14, the result of cIAP2 inactivation is the constitutive activation of the non-canonical NF-κB pathway; non-canonical NF-κB pathway signaling likely mediates resistance to treatment in these patients (Darding and Meier 2012; Foà et al. 2013; Conze, Zhao, and Ashwell 2010; Hewamana et al. 2008; Lau, Niu, and Prat 2012; Rossi et al. 2012; Rossi and Gaidano 2012; Rossi, Fangazio, and Gaidano 2012; Vallabhapurapu and Karin 2009; Zarnegar et al. 2008; Zent and Burack 2014). BIRC3 lesions are much more prevalent in relapsed and fludarabine-refractory CLL (~24%) relative to newly diagnosed CLL (~4%) (Rossi et al. 2012), although variable rates of BIRC3 mutation in CLL have been reported in other studies (0.4%–8.6%); these variations are likely due to the unselected nature of cohorts with variations in time since diagnosis (Baliakas et al. 2015; Chiaretti et al. 2014; Cortese et al. 2014; Xia et al. 2015). Additionally, BIRC3 disruptions are associated with high risk CLL and patients with BIRC3 lesions present at diagnosis had poor survival outcomes (Chiaretti et al. 2014; Foà et al. 2013; Rossi et al. 2012). BIRC3 deletion can also occur from larger deletions involving 11q; these deletions occur in 10% of patients on diagnosis and in 95% of cases encompass hundreds of genes, including BIRC3 , outside the ATM locus (Strefford 2015). However, the risk conferred by BIRC3 loss in patients with concomitant ATMloss appears to be insignificant, with ATMloss being the most important marker of poor response (Rose-Zerilli et al. 2014).

Evidence indicates that BIRC3 mutations can occur in the context of other genetic aberrations. For example, BIRC3 mutation is correlated with CLL with unmutated Immunoglobulin heavy-chain variable region genes (IGHVs) (U-CLL), trisomy 12, and 11q deletions (Baliakas et al. 2015; Chiaretti et al. 2014). However, other studies have shown that BIRC3 mutations are mutually exclusive from TP53 lesions and from 17p deletion (Baliakas et al. 2015; Rossi et al. 2012), and another study showed an inverse correlation between BIRC3 mutation and 13q deletion (Chiaretti et al. 2014).

BIRC3 mutations are associated with chemorefractoriness and poor prognosis (Rossi et al. 2012). As a result, a recent review classified CLL containing BIRC3 aberrations as very high risk, with the recommended therapeutic strategies including p53-independent drugs, BTK inhibitors, and allogenic stem cell transplantation (Puiggros, Blanco, and Espinet 2014). Recent evidence in mantle cell lymphoma has suggested that BIRC3 aberrations may result in decreased sensitivity to the BTK inhibitor ibrutinib and identified the protein kinase MAP3K14 as a potential therapeutic target in BIRC3-mutated lymphomas (Rahal et al. 2014).

Contributors: Nishitha Reddy, M.B.B.S., MSCI

Suggested Citation: Reddy, N. 2016. BIRC3 in Chronic Lymphocytic Leukemia. My Cancer Genome https://www.padiracinnovation.org/content/disease/chronic-lymphocytic-leukemia/birc3/ (Updated February 12).

Last Updated: February 12, 2016

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